New Approach to Drug Inspections

Donald D. Ashley

Director – CDER Office of Compliance

2018 FDLI Annual Meeting

May 4, 2018

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Office of Compliance Structure

Mission: The Office of Compliance shield’s patients from poor quality, unsafe, and

ineffective drugs through proactive compliance strategies and risk-based enforcement

actions.

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Agenda

• Concept of Operations and Facility Classification 90-Day Letters

• Developments in Drug Inspections: Over-the-Counter manufacturers

• New Inspection Protocol Project

• FDARA 806

• Compounding Risk Alertswww.fda.gov

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Concept of Operations (“ConOps”)

• The Program Alignment initiative created a program-based management structure that aligns staff by FDA-regulated product.

• CDER and ORA developed a ConOps that outlines how CDER Compliance, Office of Pharmaceutical Quality and ORA will work within this environment, and applies to the following types of human drug facility inspections:

– Pre- and post-approval inspections

– For-cause inspections

– Surveillance inspections

• CDER and ORA began to operationalize the ConOps in the fall of 2017

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ConOps Highlights

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What is different?

• Improved communication with stakeholders

• Defined timelines,

• 90-Day decisional letters

• 6-month goal for enforcement actions

• Parity between domestic and international

inspections

• See the ConOps Q&A at:

https://www.fda.gov/drugs/developmentappr

ovalprocess/manufacturing/ucm576309.htm

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The 90-Day Letter• Goal

• Increase engagement with industry by communicating the final inspection classification to the facility within 90 days of the end of the inspection

• Scope• Applies to any CDER-led surveillance inspection • Includes “NAI” (No Action Indicated), “VAI” (Voluntary Action

Indicated), and “OAI” (Official Action Indicated) letters

• GDUFA and ConOps• The 90-Day Letter was created to meet GDUFA II commitment

and to achieve ConOps communication goals, by Oct 1, 2018.

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The 90-Day NAI Letter

“FDA has determined that the

inspection classification of this facility

is “no action indicated (“NAI”). Based

on this inspection, this facility is

considered to be in an acceptable

state of compliance with regards to

current good manufacturing practice

(CGMP).”

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The 90-Day VAI Letter

“…Based on this inspection, this facility

is considered to be in a minimally

acceptable state of compliance…”www.fda.gov

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The 90-Day OAI Letter

“Based on this inspection, this facility is considered to be in an unacceptable state of compliance…”

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ConOps: 6 Month Enforcement Actions

• Goal• If an inspection is classified as final OAI, OMQ, solely or in collaboration

with ORA, takes an appropriate action within 3 months of the decisional letter (6 months post-inspection)

• Scope• Applies to all follow-up actions, including regulatory meetings, warning

letters, and import alerts

• Concept of Operations white paper:• “[ConOps] will enable FDA to better handle the growing complexity of the

pharmaceutical landscape and to meet new challenges by… improving the timelines for regulatory, advisory, and enforcement actions to protect public health and promote drug quality, safety, and effectiveness.”

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ConOps: Office of Compliance Progress Toward 6 Month Enforcement Actions

2015 2016 2017 2018 (Jan-Mar)

Inspection Report Received by CDER

to WL Issued

Inspection Report Received by CDER

to WL Issued

Inspection Report Received by CDER

to WL Issued

Inspection Report Received by CDER

to WL Issued

10.8 months on average

8.6 months on average

5.7 months on average

5.3 months on average

From CY 2015 to present, there has been an overall average

51% improvement

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Developments in FDA Drug Inspections: Over-the-Counter Drug Manufacturers

• FDA committed, in response to GAO, to inspect all of the previously never inspected foreign drug manufacturers over 3 years- from FY17 to FY19.

• This includes almost 1000 of the 3000 total foreign establishments.

• Many of these establishments are considered to manufacture “low-risk” OTC products, such as sunscreen and toothpaste

• FDA inspected, or removed from inventory, over 75% of these firms as of Dec. 2017

• FDA expects to have inspected, or removed, all of these firms by the end of FY18.

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Inspectional Outcomes: Over-the-Counter Drug Manufacturers

• In 2017, 39 OTC manufacturers were issued Warning Letters and 36 OTC manufacturers were added to Import Alerts

• 12 OTC manufacturers have already been issued Warning Letters in 2018*

• Some of these firms had been previously inspected, but for many it was a first inspection

• Common observations include rudimentary CGMP and OTC ophthalmic drug products with particulate issues

www.fda.gov*as of March 31, 2018

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Inspectional Outcomes: CGMP Warning Letters

0

10

20

30

40

50

60

70

80

OM

Q w

arn

ing

lett

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Calendar Year

Other

Rx

OTC

API

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4

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12

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16

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India China US Other

2017 CGMP Warning Letters by Product Class and Country

API OTC Rx Other

*To Mar. 31, 2018

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The New Inspection Protocol Project (NIPP)

NIPP is a collaborative effort between the FDA’s Office of Regulatory Affairs and Center for Drug Evaluation and Research. NIPP was launched to support the advancement of pharmaceutical quality by developing a new, more efficient inspection and reporting paradigm to better assess and record the state of quality in manufacturing facilities.

Areas of protocol and guidance development under NIPP:

• Surveillance inspections

• Pre-approval inspections• Evidence development

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• The NIPP Surveillance, Pre-Approval, and Evidence Development

working groups currently have pilots underway.

• These pilots are designed to assess the protocols and guidance:

• Usability - the time and level of effort the draft protocols / guidance

require of inspection personnel

• Usefulness - the quality of information collected, developed, and

reported during inspections to be used by surveillance, pre-approval,

and compliance personnel post-inspection.

• The Evidence Development pilot is focused on guidance applicable to all

CGMP inspections.

NIPP - Status of Work

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NIPP - Evidence Development• This working group’s efforts are intended to increase the efficiency of

compliance review by making it easier to prioritize based on risk. This is

incredibly important work because the Agency’s CGMP compliance workload

continually increases.

• How will this be accomplished?

• Evidence Development guidance and work aids will highlight the

development of information useful in assessing the potential for product

quality and consumer impact.

• These will help investigators understand of aggravating or mitigating

circumstances that affect the risk associated with specific CGMP

violations.

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FDARA Overview• FDA Reauthorization Act of 2017 (FDARA) reauthorized GDUFA

II (in addition to other UFAs)

– included several generics-related legislative “riders”

• FDARA went into effect on August 18, 2017, prior to start of GDUFA II on October 1, 2017

• Section 806 of FDARA adds a new requirement for FDA to generate and implement a protocol for expedited review of responses to inspectional observations, where the inspectional observations are the only barrier to approval of certain drug applications.

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FDARA Sec. 806. InspectionsSEC. 806. INSPECTIONS.

Within 6 months of the date of enactment of this Act, the Secretary of Health and Human Services shall develop and implement a

protocol for expediting review of timely responses to reports of observations from an inspection under section 704 of the

Federal Food, Drug, and Cosmetic Act (21 U.S.C. 374). Such protocol shall—

(1) apply to responses to such reports pertaining to applications submitted under section 505 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 355)—

(A) for which the approval is dependent upon remediation of conditions identified in the report;

(B) for which concerns related to observations from an inspection under such section 704 are the only barrier to approval;

and

(C) where the drug that is the subject of the application is a drug—

(i) for which there are not more than 3 other approved applications under section 505(j) of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 355(j)) that reference the same listed drug and for which there are less than 6 abbreviated new

drug applications tentatively approved; or

(ii) that is included on the list under section 506E of such Act (21 U.S.C. 356e);

(2) address expedited re-inspection of facilities, as appropriate; and

(3) establish a 6-month timeline for completion of review of such responses to such reports.

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Compounding Risk Alerts: Rapid Communication of Inspectional Findings

• FDA began in 2017 to post “compounding risk alerts” to inform healthcare practitioners of adverse event reports associated with compounded drugs. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm570188.htm

• FDA inspections or other actions may be are initiated when FDA receives adverse event reports from healthcare practitioners, patients, and others.

• FDA provides information in compounding risk alerts to health care professionals to further the goal of protecting patients from unsafe, ineffective, and poor quality compounded drugs.

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Compounding Risk Alerts2017: eye injections of a compounded drug linked to vision problems in 43 patients

• At least 43 patients received eye injections of a drug containing triamcinolone (steroid) and moxifloxacin (anti-infective) compounded by a Texas pharmacy.

• Patients developed vision impairment (blurred or decreased vision), loss of color perception, glare, halos, pain, and loss of balance among other symptoms.

• FDA alert: https://www.fda.gov/Drugs/DrugSafety/ucm569114.htm

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Compounding Risk Alerts2017: compounded curcumin product linked to one illness and one death

• Two patients given infusions of curcumin (a component of turmeric) compounded with polyethylene glycol (PEG) 40 castor oil experienced hypersensitivity reactions. One patient subsequently died.

• Risks illustrated by this case include the

– Lack of a label warning about hypersensitivity reactions associated with PEG 40 castor oil

– Use of a non-pharmaceutical grade ingredient containing impurities such as diethylene glycol

– IV administration of curcumin when its safety profile by this route of administration and its effectiveness in treating eczema and thrombocytopenia have not been established

• FDA Alert: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ PharmacyCompounding/ucm570192.htm

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THANK YOU

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